The Autoimmune Disease-associated PTPN22 Variant Promotes Calpain-mediated Lyp/Pep Degradation Associated with Lymphocyte and Dendritic Cell Hyperresponsiveness

Overview

Journal Nat Genet

Specialty Genetics

Date 2011 Aug 16

PMID 21841778

Citations 152

Authors

Jinyi Zhang

Naima Zahir

Qiuhong Jiang

Helen Miliotis

Stephanie Heyraud

Xianwang Meng

Baoxia Dong

Gang Xie

Frank Qiu

Zhenyue Hao

Christopher A McCulloch

Edward C Keystone

Alan C Peterson

Katherine A Siminovitch

Affiliations

Soon will be listed here.

Abstract

A variant of the PTPN22-encoded Lyp phosphatase (Lyp620W) confers risk for autoimmune disease, but the mechanisms underlying this association remain unclear. We show here that mice expressing the Lyp variant homolog Pep619W manifest thymic and splenic enlargement accompanied by increases in T-cell number, activation and positive selection and in dendritic- and B-cell activation. Although Ptpn22 (Pep) transcript levels were comparable in Pep619W and wild-type Pep619R mice, Pep protein levels were dramatically reduced in the mutant mice, with Pep619W protein being more rapidly degraded and showing greater association with and in vitro cleavage by calpain 1 than Pep619R. Similarly, levels of the Lyp620W variant were decreased in human T and B cells, and its calpain binding and cleavage were increased relative to wild-type Lyp620R. Thus, calpain-mediated degradation with consequently reduced Lyp/Pep expression and lymphocyte and dendritic cell hyperresponsiveness represents a mechanism whereby Lyp620W may increase risk for autoimmune disease.

Citing Articles

Regulation of T Cell Signaling and Immune Responses by PTPN22.

Brownlie R, Salmond R Mol Cell Biol. 2024; 44(10):443-452.

PMID: 39039893 PMC: 11486154. DOI: 10.1080/10985549.2024.2378810.

Genetic and Epigenetic Aspects of Type 1 Diabetes Mellitus: Modern View on the Problem.

Minniakhmetov I, Yalaev B, Khusainova R, Bondarenko E, Melnichenko G, Dedov I Biomedicines. 2024; 12(2).

PMID: 38398001 PMC: 10886892. DOI: 10.3390/biomedicines12020399.

The Tyrosine Phosphatase Activity of PTPN22 Is Involved in T Cell Development via the Regulation of TCR Expression.

Bai B, Li T, Zhao J, Zhao Y, Zhang X, Wang T Int J Mol Sci. 2023; 24(19).

PMID: 37833951 PMC: 10572452. DOI: 10.3390/ijms241914505.

Glucose-6-phosphate dehydrogenase deficiency and long-term risk of immune-related disorders.

Israel A, Schaffer A, Berkovitch M, Ozeri D, Merzon E, Green I Front Immunol. 2023; 14:1232560.

PMID: 37753082 PMC: 10518697. DOI: 10.3389/fimmu.2023.1232560.

Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency and Long-Term Risk of Immune-Related diseases.

Israel A, Schaffer A, Berkovitch M, Ozeri D, Merzon E, Green I medRxiv. 2023; .

PMID: 37090544 PMC: 10120794. DOI: 10.1101/2023.03.23.23287616.

References

Cloutier J, Veillette A . Cooperative inhibition of T-cell antigen receptor signaling by a complex between a kinase and a phosphatase. J Exp Med. 1999; 189(1):111-21. PMC: 1887684. DOI: 10.1084/jem.189.1.111. View

Vang T, Congia M, Macis M, Musumeci L, Orru V, Zavattari P . Autoimmune-associated lymphoid tyrosine phosphatase is a gain-of-function variant. Nat Genet. 2005; 37(12):1317-9. DOI: 10.1038/ng1673. View

Cloutier J, Veillette A . Association of inhibitory tyrosine protein kinase p50csk with protein tyrosine phosphatase PEP in T cells and other hemopoietic cells. EMBO J. 1996; 15(18):4909-18. PMC: 452228. View

Poueymirou W, Auerbach W, Frendewey D, Hickey J, Escaravage J, Esau L . F0 generation mice fully derived from gene-targeted embryonic stem cells allowing immediate phenotypic analyses. Nat Biotechnol. 2006; 25(1):91-9. DOI: 10.1038/nbt1263. View

Mykles D . Intracellular proteinases of invertebrates: calcium-dependent and proteasome/ubiquitin-dependent systems. Int Rev Cytol. 1998; 184:157-289. DOI: 10.1016/s0074-7696(08)62181-6. View

Hill R, Zozulya S, Lu Y, Ward K, Gishizky M, Jallal B . The lymphoid protein tyrosine phosphatase Lyp interacts with the adaptor molecule Grb2 and functions as a negative regulator of T-cell activation. Exp Hematol. 2002; 30(3):237-44. DOI: 10.1016/s0301-472x(01)00794-9. View

Sandoval A, Oviedo N, Tadmouri A, Avila T, De Waard M, Felix R . Two PEST-like motifs regulate Ca2+/calpain-mediated cleavage of the CaVbeta3 subunit and provide important determinants for neuronal Ca2+ channel activity. Eur J Neurosci. 2006; 23(9):2311-20. PMC: 2700823. DOI: 10.1111/j.1460-9568.2006.04749.x. View

Naldini L . Lentiviruses as gene transfer agents for delivery to non-dividing cells. Curr Opin Biotechnol. 1998; 9(5):457-63. DOI: 10.1016/s0958-1669(98)80029-3. View

Zikherman J, Hermiston M, Steiner D, Hasegawa K, Chan A, Weiss A . PTPN22 deficiency cooperates with the CD45 E613R allele to break tolerance on a non-autoimmune background. J Immunol. 2009; 182(7):4093-106. PMC: 2765978. DOI: 10.4049/jimmunol.0803317. View

10.

Velaga M, Wilson V, Jennings C, Owen C, Herington S, Donaldson P . The codon 620 tryptophan allele of the lymphoid tyrosine phosphatase (LYP) gene is a major determinant of Graves' disease. J Clin Endocrinol Metab. 2004; 89(11):5862-5. DOI: 10.1210/jc.2004-1108. View

11.

Bottini N, Musumeci L, Alonso A, Rahmouni S, Nika K, Rostamkhani M . A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes. Nat Genet. 2004; 36(4):337-8. DOI: 10.1038/ng1323. View

12.

Arechiga A, Habib T, He Y, Zhang X, Zhang Z, Funk A . Cutting edge: the PTPN22 allelic variant associated with autoimmunity impairs B cell signaling. J Immunol. 2009; 182(6):3343-7. PMC: 2797545. DOI: 10.4049/jimmunol.0713370. View

13.

Saxena M, Williams S, Hammi D, Mustelin T . Characterization of TCR-induced receptor-proximal signaling events negatively regulated by the protein tyrosine phosphatase PEP. Eur J Immunol. 1999; 29(12):3845-54. DOI: 10.1002/(SICI)1521-4141(199912)29:12<3845::AID-IMMU3845>3.0.CO;2-U. View

14.

Chien W, Tidow N, Williamson E, Shih L, Krug U, Kettenbach A . Characterization of a myeloid tyrosine phosphatase, Lyp, and its role in the Bcr-Abl signal transduction pathway. J Biol Chem. 2003; 278(30):27413-20. DOI: 10.1074/jbc.M304575200. View

15.

Decker P, Kotter I, Klein R, Berner B, Rammensee H . Monocyte-derived dendritic cells over-express CD86 in patients with systemic lupus erythematosus. Rheumatology (Oxford). 2006; 45(9):1087-95. DOI: 10.1093/rheumatology/kel061. View

16.

Villadangos J, Schnorrer P . Intrinsic and cooperative antigen-presenting functions of dendritic-cell subsets in vivo. Nat Rev Immunol. 2007; 7(7):543-55. DOI: 10.1038/nri2103. View

17.

Oene M, Wintle R, Liu X, Yazdanpanah M, Gu X, Newman B . Association of the lymphoid tyrosine phosphatase R620W variant with rheumatoid arthritis, but not Crohn's disease, in Canadian populations. Arthritis Rheum. 2005; 52(7):1993-8. DOI: 10.1002/art.21123. View

18.

Wang N, Chen W, Linsel-Nitschke P, Martinez L, Agerholm-Larsen B, Silver D . A PEST sequence in ABCA1 regulates degradation by calpain protease and stabilization of ABCA1 by apoA-I. J Clin Invest. 2003; 111(1):99-107. PMC: 151839. DOI: 10.1172/JCI16808. View

19.

Hasegawa K, Martin F, Huang G, Tumas D, Diehl L, Chan A . PEST domain-enriched tyrosine phosphatase (PEP) regulation of effector/memory T cells. Science. 2004; 303(5658):685-9. DOI: 10.1126/science.1092138. View

20.

Rieck M, Arechiga A, Onengut-Gumuscu S, Greenbaum C, Concannon P, Buckner J . Genetic variation in PTPN22 corresponds to altered function of T and B lymphocytes. J Immunol. 2007; 179(7):4704-10. DOI: 10.4049/jimmunol.179.7.4704. View